Marine-Inspired Antimicrobial Peptides Disrupt Gene Expression at the DNA Level

TL;DR

Scientists discovered two new antimicrobial peptides that disrupt bacterial DNA and stop protein production, offering a new approach to fight infections.

Contribution

The study reveals a novel DNA-targeting mechanism for antimicrobial peptides, bypassing traditional membrane disruption.

Findings

L3 and L3-K peptides caused significant changes in bacterial protein expression, affecting metabolism and transport.

Both peptides inhibited DNA transcription and translation, with L3 showing stronger DNA binding.

The peptides' antimicrobial activity is directly linked to their DNA-binding and interference with information processing.

Abstract

Genome mining of Streptomyces sp.
H-KF8 combined with sequence engineering yielded two serum-stable,
noncytotoxic, nonlytic antimicrobial peptides, L3 and L3-K. Initial
studies in uropathogenic Escherichia coli suggested membrane effects and nucleoid relaxation, prompting a
comprehensive investigation of their mode of action. In this study
tandem mass tag (TMT)-based quantitative proteomics revealed extensive
proteome remodeling, with 175 and 120 differentially expressed proteins
(DEPs) after treatment with L3 and L3-K, respectively. L3 induced
predominantly upregulated responses linked to metabolism, RNA processing,
transport, and homeostasis, whereas L3-K mainly caused the downregulation
of proteins involved in metabolism, transport, and cell structure.
Both peptides disrupted ABC transporter-mediated nutrient uptake and
elicited stress responses, while L3 specifically perturbed the mal regulon, indicative of broader transcriptional dysregulation.
Complementary fluorescent dye displacement and in vitro transcription/translation
assays demonstrated nonspecific DNA binding, stronger for L3 than
L3-K, and potent inhibition of transcriptional and translational processes.
Strikingly, inhibitory concentrations paralleled their minimum inhibitory
concentrations, directly linking DNA binding and interference with
central information processing to antimicrobial activity. These findings
reveal that L3 and L3-K primarily act by targeting DNA and interfering
with the transcription-translation machinery. Beyond offering mechanistic
insights, this study underscores peptides’ potential to act
as scaffolds for next-generation antimicrobial peptides with DNA-binding
and nonmembrane-lytic activity.

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